15 December 2016

Image: An image of fission yeast cells in the process of cell division. Fission yeast cells are related to human cells but are much simpler, making experiments faster and easier to interpret. Importantly, many of the key discoveries in cell biology occur in yeast before being confirmed in humans.

Francis Crick Institute scientists led by Sir Paul Nurse have
resolved a long-standing debate in the field of cell cycle science.
In doing so, they have revised the textbook explanation for how the
process of cell division is controlled by a protein called CDK.

CDK stands for Cyclin-Dependent Kinase. The discovery of this
family of proteins won Paul Nurse, Director of the Crick, a share
of the 2001 Nobel Prize in Physiology or Medicine.

Now, his lab has found convincing evidence for the 'activity
threshold model' for CDK. This model proposes that CDK controls
cell division simply by turning on the proteins needed at different
stages of the process based on increases in its own activity
level.

Matthew Swaffer, in Paul Nurse's lab, explains: "When a cell
divides, it has to replicate its DNA (S-phase) before it then
separates the DNA into two daughter cells (mitosis). The correct
timing of these two events is critical as incorrect replication or
separation of DNA can cause dangerous mutations that might help
cancer cells to escape the checks and balances that control
division.

"S-phase and mitosis are controlled by CDK, a master-regulator
enzyme that changes other proteins inside the cell by chemically
adding a phosphate group to them. This process is called
phosphorylation and it works like a switch to turn on the protein
which is being modified."

Because human cells are very complex, the researchers studied
fission yeast, which is simpler and easier to manipulate. This
allowed them to re-engineer CDK to directly test their theory. They
combined this approach with a sophisticated technology called
phosphoproteomics. Co-authour Bram Snijders, also at the Crick,
explained that "the powerful phosphoproteomics approach enables
measurement of the phosphorylation levels of thousands of proteins
at the same time".

The team found that different proteins are phosphorylated, and
therefore turned on, at different times during the course of cell
division. Via phosphorylation, CDK turns on proteins involved in
the S-phase early in cell division, while proteins necessary for
mitosis are switched on later.

Importantly, the scientists discovered that the time at which
different proteins are phosphorylated is determined only by the
activity levels of CDK itself. S-phase proteins are switched on
earlier because they are easier for CDK to modify and become
phosphorylated when the activity of CDK is still low at the start
of cell division. Later in the process, after the enzyme activity
of CDK has increased, the proteins involved in mitosis are
phosphorylated by the higher CDK levels.

Dr Swaffer says: "The 'activity-threshold model' was first
proposed in 1996 in Paul's lab. However, for the past 20 years it
was not widely thought to be central to the process of controlling
cell division. This study provides direct evidence to support this
model and answers a number of key questions in the field.

"Understanding how CDK regulates cell division in yeast tells us
a lot about how the same processes work in human cells, which is
central to our understating of cancer because cancers arise when
cells divide uncontrollably."

Francis Crick Institute scientists have found key evidence for
how CDK, the 'master regulator' of cell division, switches on
different proteins at different stages in the process. Their
findings oppose the currently accepted explanation for CDK's
mechanism.

The work is important because CDK keeps cell division on track
- but cancer can result when cell division goes awry.

This Crick-funded work was also supported by the Wellcome
Trust, the Leonard and Estelle Wolfson Foundation and the Breast
Cancer Research Foundation in the USA.

The Francis Crick Institute is a unique partnership between the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King's College London.

The Francis Crick Institute Limited is a registered charity in England and Wales no. 1140062 and a company registered in England and Wales no. 06885462, with its registered office at 1 Midland Road, London NW1 1AT.